Allergen immunotherapy

Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for some types of allergies. It is useful for environmental allergies, allergies to insect bites, and asthma.[1][2] Its benefit for food allergies is unclear and thus not recommended.[1] Immunotherapy involves exposing people to larger and larger amounts of allergen in an attempt to change the immune system's response.[1]

Meta-analyses have found that injections of allergens under the skin are effective in the treatment in allergic rhinitis in children[3][4] and in asthma.[2] The benefits may last for years after treatment is stopped.[5] It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects.[6] The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong.[5] In this form the allergen is given under the tongue and people often prefer it to injections.[5] Immunotherapy is not recommended as a stand-alone treatment for asthma.[5]

Side effects during treatment are usually local and mild and can usually be eliminated by adjusting the dosage. Anaphylaxis has occurred on rare occasions and this is why treatment should only be administered in a medical environment.[7]

Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved. It is currently being studied as a possible treatment for eczema and food allergies in children.

Subcutaneous immunotherapy, also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by monthly maintenance injections for a period of 3–5 years.[8] Although efficacy of subcutaneous immunotherapy has been demonstrated by several studies, it entails the risk of systemic anaphylactic reactions.[9] Hence the necessity for it to be performed by clinicians trained in allergy.

Oral immunotherapy (OIT) involves giving the allergen by mouth. Its balance of risk to benefit for food allergies is not well studied, and thus is only recommended as an experimental treatment as of 2015.[1]

OIT is currently under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended.[11][12] However, almost every study has excluded people with severe allergen-induced anaphylaxis.[13]

In desensitization immunotherapy the aim is to induce or restore tolerance to the allergen by reducing its tendency to induce IgE production. Patients are desensitized through the administration of escalating doses of allergen that gradually decreases the IgE-dominated response. The objective of immunotherapy is to direct the immune response away from humoral immunity and toward cellular immunity, thereby encouraging the body to produce less IgE antibodies and more Th1 regulatory T cells, which secrete IL-10 and/or TGF-beta, which skew the response away from IgE production.[14]

OIT also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction.[12][13]

Reactivity is tested using oral food challenges or with skin prick tests. Phases 1&2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home.[12]

In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific.

The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in a patient cohort. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Mary’s Hospital in London, published their findings in The Lancet in 1911.[15][16] Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that hay fever patients “sometimes become cured” and that this was possibly because they “have had the good fortune to develop an active immunity against the toxin.” He hypothesized that by injecting hay fever patients with small amounts of a pollen “toxin”, a state of immunity could be achieved.[17]

After the groundbreaking work by Noon and Freeman in the UK and by Cooke and colleagues in the US, allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s.

Later, sublingual formulations were found to be effective in symptom reduction in allergic rhinitis. Sublingual immunotherapy is also found to have a better safety profile than subcutaneous immunotherapy since the local side effects caused by sublingual immunotherapy contrasted with the possible systemic events that can occur with the subcutaneous immunotherapy.

As the clinical evidence accumulated, the use of sublingual immunotherapy became incorporated into major international guidelines. In a position paper published by a scientific society (by WHO in 1981 then by the ARIA consensus in 2002), sublingual immunotherapy’s established efficacy and a favourable safety profile were quoted.

In 2001, scientific guidelines confirmed and extended the indication of sublingual immunotherapy also to children. The guidelines acknowledge that sublingual immunotherapy is safer than subcutaneous immunotherapy.

World Allergy Organisation Position Paper in 2009 on sublingual immunotherapy emphasized the benefits of licensing allergen immunotherapy as a therapeutic class.

By following the advice of the experts in reconsidering the role of allergen immunotherapy, the European Medicines Agency issued in 2009 new recommendations concerning the clinical development, production and quality of immunotherapy products with a view to register allergen immunotherapy as pharmaceutical specialties.

Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common.[18] In 2014, the FDA approval a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis).[19]

A variety of new approaches are currently being tested to improve efficacy of oral immunotherapy.

One approach being studied is in altering the protein structure of the allergen to decrease immune response while still developing tolerance for the patient. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution. In one study, subjects allergic to milk were 16x more likely to develop complete milk tolerance compared to complete milk avoidance. Another approach regarding changes in protein is to change specific amino acids in the protein to decrease recognition of the allergen by allergen-specific antibodies.[13]

Another approach to improving oral immunotherapy is to change the immune environment to prevent TH2 cells from responding to the allergens during treatment. For example, drugs that inhibit IgE-mediated signaling pathways can be used in addition to OIT to reduce immune response. In 1 trial, the monoclonal antibodyomalizumab was combined with high-dose milk oral immunotherapy and saw positive results. Several other trials are also currently being done combining omalizumab with OIT for a variety of food allergens. FAHF-2, a Chinese herbal mixture, has shown positive effects on the immune system and has been shown to protect mice from peanut-induced anaphylaxis. FAHF-2 was also well tolerated in a phase I study. While it is possible that omalizumab, FAHF-2 or other immunomodulatory agents alone might be able to treat dangerous allergies, combining these with OIT may be more effective and synergistic, warranting further investigation.[13]

In addition, nanoparticles is a field of development that can be used for OIT. With the potential to modulate antigen release, it may one day be possible to take a pill containing nanoparticles that will modulate dosing, requiring fewer office visits.[13]

Studies have also been done to determine the efficacy of OIT for multiple allergens simultaneously. One study concluded that multi-OIT would be possible and relatively, though larger studies would be necessary.[20]